UV injury dramatically changes the microenvironment of the skin causing distinct monocyte(Mo) behavior in normal and UV in vivo milieus. The post UV milieu promotes Mo-macrophages(Mph) and suppresses dendritic cell(DC) antigen presenting cells(APC's) maturation. UV-induced immunosuppression is associated with complement component iC3b deposition in the skin, and reversal of immunosuppression occurs in mice treated with antibodies to CD11b (an iC3b receptor on immunosuppressive Mo APC's), and in mice treated with sCR1 prevents iC3b formation). Mo exposed to iC3b model the in vivo situation; they are induced to express Mo/Mph features and are arrested in DC development, yet retain DC precursor potential. Recent data suggest that the p38 MAP kinase signaling pathway is involved in DC maturation, counterbalanced by ERK MAP kinase, and that CD11b engagement by antibodies activates ERK. Thus, it was interesting in our preliminary data that MAPK signaling pathway-induced transcripts were very prominently upregulated following iC3b engagement of monocyte CD11b. Also very prominently upregulated was the Oncostatin M/IL-6 family receptor/SOCS3 signaling pathway, which can preferentially promote Mph over DC, and which interacts with ERK. Thus, the hypothesis to be tested is whether these signaling pathways represent the critical mechanism by which iC3b mediates Mo differentiation and, ultimately, UV-induced immune suppression. Aim I examines MAPK activation and utilizes chemical and dominant negative MAPK inhibitors and MAPK overexpression strategies to determine if iC3b critically alters the balance of p38/ERK signaling during Mo differentiation. Aim II tests whether the SOCS3/IL6 receptor family signaling cascade is critically involved in the mechanism of iC3b modification of Mo precursors to DC and Mph's, and the linkage of MAPK's in the pathway. Aim III translates these findings in vivo to confirm their role in integrated immune response regulation, leading to novel immunotherapeutic strategies with clinical impact.